Women and Coronary Artery Disease (CAD)

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Women and Coronary Artery Disease (CAD)

• What do we need to know ?
• Dr. R.V.S.N.Sarma, M.D., M.Sc., (Canada)
• Consultant Physician and Chest Specialist
• Thiruvallur, Chennai

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Myths vs Facts
Myths Facts
Men are more likely to have heart disease Heart disease is the 1 killer of men and women 50,000 more women than men die of heart disease every year
Cancer is a bigger threat than heart disease Nearly twice as many US women die from heart disease and stroke than from all cancers combined
Doctors are aware of womens risk for heart disease and act accordingly Undertreatment and underdiagnosis of heart disease in women contributes to excess mortality in women
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Womens Perceptions of Heart Disease

• 72 of young women (ages 25-40) still consider
  cancer to be the greatest threat to womens
  health
• Some women know about the risks of heart disease
  but do not hear it from their own doctors and do
  not personalize it
• 65 of women recognize that symptoms may be
  atypical but do not know classic symptoms
• Most women learn about coronary artery disease
  (CAD) from magazines and the Webnot from their
  own physicians!

Robinson A. Circulation. 2001
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Gender Bias in the Treatment of Women

• The community has viewed womens health almost
  with a bikini approach, looking essentially at
  the breast and reproductive system, and almost
  ignoring the rest of the woman as part of womens
  health . Nanette Wenger, MD Chief of
  Cardiology, Grady Hospital Professor of
  Medicine, Emory University Atlanta, Georgia

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Magnitude of the Problem

• 2.5 million women per year in the US are
  hospitalized with cardiovascular disease (CVD)
• Deaths from CVD 500,000/yr
• Leading cause of death in US women CAD
• gt230,000 women die from CAD each year
• 1990 US Congress directed the National
  Institutes of Health that women be included in
  clinical trials and that gender differences be
  evaluated

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Women in Clinical Trials

• Women are underrepresented in cardiovascular (CV)
  trials
• Evidence-based CV medicine biased toward men
• Food and Drug Administration/National Institutes
  of Health mandate 50 enrollment of women
• Women need to be empowered to enroll in clinical
  trials for heart disease
• Breast-cancer awareness is a good example

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Publication Bias Gender Representation and
Negative Studies

• 1966-1994 noninvasive testing literature
• 8 to 27 women
• Lower diagnostic accuracy in women
• High false-positive rates
• Inability to perform maximal stress

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CVD Mortality Trends (1979-1999)
Deaths in Thousands
American Heart Association. 2002 Heart and Stroke
Statistical Update. 2001
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Prevalence of CVD in the US
American Heart Association. 2002 Heart and Stroke
Statistical Update. 2001
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Deaths From CVD and Cancer by Age and Sex
Anderson RN. National Vital Statistics Reports.
2002
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Deaths From CVD (1999)
American Heart Association. 2002 Heart and Stroke
Statistical Update. 2001
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Health Threats to Women Perception vs Reality
1
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1. Gallup survey. 1995 2. American Heart
Association. Heart Stroke Facts. 1996
Statistical Supplement
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Death From Breast Cancer or Heart Disease in
Women in the US
US Vital Statistics, 1990
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Statistics for Women

• 503,927 died of CVD in 1998
• 226,467 from heart attack or other cardiac events
• 97,303 from stroke
• 1 in 5 women has some form of CVD
• 38 of women who have a heart attack die within
  1 year
• 40 of coronary events in women are fatal
• Most occur without prior warning

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Women and Coronary Artery Disease (CAD)

• Risk Factors and Gender Differences

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Warning Signs and Symptoms of CAD
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Gender Differences in Heart Attack Symptoms

• Typical in both sexes
• Pain, pressure, squeezing, or stabbing pain in
  the chest
• Pain radiating to neck, shoulder, back, arm, or
  jaw
• Pounding heart, change in rhythm
• Difficulty breathing
• Heartburn, nausea, vomiting, abdominal pain
• Cold sweats or clammy skin
• Dizziness

• Typical in women
• Milder symptoms (without chest pain)
• Sudden onset of weakness, shortness of breath,
  fatigue, body aches, or overall feeling of
  illness (without chest pain)
• Unusual feeling or mild discomfort in the back,
  chest, arm, neck, or jaw (without chest pain)

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Less Common Heart Attack Symptoms in Women

• Milder symptoms without accompanying chest pain
• Sudden onset of weakness, shortness of breath,
  fatigue, body aches, overall feeling of illness
• Burning sensation in the chest, may be mistaken
  as heartburn
• An unusual feeling or mild discomfort in the
  back, chest, arm, neck, or jaw

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Major Risk Factorsfor Heart Disease
Modifiable Nonmodifiable Emerging Risk Factors
High blood pressure Family history Homocysteine
Abnormal cholesterol levels Age Elevated lipoprotein (a) levels
Diabetes Gender Clotting factors
Cigarette smoking Markers of inflammation (CRP)
Obesity
Physical inactivity
Grundy SM, et al. Circulation. 1998 Grundy SM.
Circulation. 1999 Braunwald E. N Engl J Med.
1997 Grundy SM, et al. J Am Coll Cardiol. 1999
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Emerging Risk Factors

• Lipoprotein (a)
• Homocysteine
• Prothrombotic factors
• Proinflammatory factors
• Impaired fasting glucose
• Subclinical atherosclerosis
• Other clinical forms of atherosclerotic disease
  (peripheral arterial disease, abdominal aortic
  aneurysm, and symptomatic carotid artery disease)
• Abnormal internal or common carotid CIT,
  ankle-arm index lt0.9, coronary Ca2

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Diabetes Creates Higher Risks for Women With CAD

• 65 of diabetics die from heart disease or stroke
• 4.2 million American women have diabetes
• Diabetes increases CAD risk 3-fold to 7-fold in
  women vs 2-fold to 3-fold in men
• Diabetes doubles the risk of second heart attack
  in women but not in men
• Every year, heart disease kills 50,000 more
  American women than men
• Statistics are particularly high among African
  American women

American Heart Association Centers for Disease
Control and Prevention Manson JE, et al.
Prevention of Myocardial Infarction. 1996
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Lowest Survival Rates for Diabetic Women

• CAD mortality rates in diabetics, especially
  women, have not decreased to the same extent as
  those in the general population
• In a large cohort referred for coronary disease,
  diabetic women had the highest mortality rates
• Estimate of ischemic burden with stress
  myocardial perfusion imaging significantly
  improved risk stratification in diabetic women
  compared with clinical risk alone
• Stratification by the number of ischemic vessels
  demonstrated a significant linear increase in
  cardiac events with escalating ischemic burden
  (sex-diabetes interaction, P .016)

Gu K, et al. JAMA. 1999 Giri S, et al.
Circulation. 2002
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Diabetes Powerful Risk Factor for CAD in Women

• Framingham Heart Study
• Women with diabetes mellitus had relative risk of
  5.4 for CAD vs women without diabetes
• Men with diabetes had relative risk of 2.4
• Nurses Health Study
• Relative risk of 6.3 for total cardiovascular
  (CV) mortality
• Even if women had diabetes for lt4 years, their
  risk of CAD was significantly elevated

Kannel W. Am Heart J. 1987 Manson J, et al. Arch
Intern Med. 1991
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Clinical Identification of the Metabolic Syndrome

• Abdominal obesity
• Men gt88 cm (gt40 in)
• Women gt80 cm (gt35 in)
• Triglycerides (TG) gt150 mg/dL
• HDL cholesterol
• Women lt50 mg/dL
• Men lt40 mg/dL
• Blood pressure gt130/gt85 mm Hg
• Fasting glucose gt100 mg/dL

National Heart, Lung, and Blood Institute
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Impact of Triglyceride Levels on Relative Risk
of CAD
Castelli WP. Can J Cardiol. 1988
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Women and CAD Risk Factors

• Higher prevalence of avoidable risk factors1
• ? blood cholesterol, ? TG
• ? physical inactivity
• ? overweight (body mass index, 25.0-29.9)
• Diabetes is a more powerful risk factor for CAD2
• 3- to 7-fold in women vs 2- to 3-fold in men
• ? HDL cholesterol levels more predictive of CAD2
• Women counseled less about nutrition, exercise,
  and weight control2

1. American Heart Association. 1999 Heart and
Stroke Statistical Update. 1998 2. Mosca L, et
al. Circulation. 1999
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MI or Death Often First Sign of CAD
Levy D, et al. Textbook of Cardiovascular
Medicine. 1998
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Smoking

• Single most preventable cause of death in US
• Smoking by women causes 150 more deaths from
  heart disease than lung cancer
• Women who smoke are 2-6 times more likely to
  suffer a heart attack
• Use of birth control pills in smokers compounds
  cardiac risk

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Overweight
American Heart Association. 2002 Heart and Stroke
Statistical Update. 2001
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Physical Inactivity

• Lack of exercise is a proven risk factor for
  heart disease
• A lack of regular physical exercise is a growing
  epidemic all over the world. We seem to eat much
  more than what we burn
• Heart disease is twice as likely to develop in
  inactive people than in those who are more active
• Physical activity helps maintain weight, blood
  pressure, and diabetes
• Women should exercise to increase heart rate for
  20-30 minutes a day, 3-5 times per week

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Hormonal Effects on Ischemia and Disease
Prevalence

• Premenopause
• Estrogen has digoxin-like effect ? ST ?
• Post-menopause effect on HRT
• ? ST ? - vasodilatory effects of HRT
• Increase exercise duration/decrease chest pain
• Women with intact uterus take progestin to
  protect against uterine malignancies
• Estrogen and medroxyprogesterone attenuate this
  effect

Lloyd GW, et al. Heart. 2000 Webb CM, et al.
Lancet. 1998 Morise AP, et al. Am J Cardiol.
1993 Rosano GM, et al. J Am Coll Cardiol. 2000
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Hormonal Effects on Ischemia and Disease
Prevalence

• Estrogen modulates chest pain syndromes
• Premenopausal CAD angina/ischemia variation by
  menstrual cycle
• Early follicular phase estradiol and
  progesterone levels - low lt time to ischemia
  onset
• Mid-cycle estrogen levels - highest gt time to
  ischemia onset

Lloyd GW, et al. Heart. 2000 Webb CM, et al.
Lancet. 1998 Morise AP, et al. Am J Cardiol.
1993 Rosano GM, et al. J Am Coll Cardiol. 2000
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Postmenopausal Hormone Therapy and
Cardioprotection

• First randomized trial
• HERS trial (Heart and Estrogen/Progestin
  Replacement Study)
• Secondary CAD prevention trial
• Randomized trial of placebo vs estrogen and
  medroxyprogesterone
• Follow-up 4 years
• N 2,763 women with an intact uterus
• Outcome measures
• Primary nonfatal MI or cardiac death
• Secondary unstable angina, coronary
  revascularization, congestive heart failure

HERS trial. JAMA. 1998.
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Is There a Role for HRT?

• Secondary prevention
• 1998 HERS
• 4 years of treatment with conjugated estrogen
  plus medroxyprogesterone acetate
• No reduction in the risk of MI and coronary death
  in women with established CAD

HERS trial. JAMA. 1998.
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Is There a Role for HRT?

• Secondary prevention
• 3/2000 Estrogen Replacement and Atherosclerosis
  trial (ERA)
• 309 postmenopausal women with CAD
• Placebo vs conjugated estrogen (.625 mg/day) vs
  conjugated estrogen (.625 mg/day) with
  medroxyprogesterone acetate (2.5 mg/day)
• Angiographic analysis of the diameter of the
  coronary arteries at the start of the study and 3
  years later
• ERA trial results at follow-up angiography
• The progression of coronary atherosclerosis was
  unchanged in the women randomized to either of
  the estrogen groups

ERA trial. J Am Coll Cardiol. 2001
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Is There A Role for HRT?

• Primary prevention
• Womens Health Initiative. WHI trial
• 160,000 women1991-2005
• Initial results no cardioprotection attributed
  to HRT in women on HRT
• American Heart Association HRT not recommended
  for primary or secondary cardioprotection

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Conclusions Risk Factor Management

• CVD begins in childhood and is strongly
  associated with major risk factors for heart
  disease
• Multiple risk factors require more aggressive
  management
• Aggressive risk-factor modification (often with
  multiple medications) is the most effective
  strategy for reducing the consequences of heart
  disease

Berenson GS, et al. N Engl J Med. 1998. Neaton
JD, et al. Arch Intern Med. 1992. Kannel WB. in
Atherosclerosis and Coronary Artery Disease.
1996. Grundy SM, et al. Circulation. 1999
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Gender Differences in CAD Risk Factors

• Increasing recognition that atherosclerosis is an
  inflammatory process
• Ridker PM, et al A prospective case-controlled
  study among 28,263 postmenopausal women
• Among 12 markers of inflammation, C reactive
  protein was the strongest univariate predictor of
  the risk of CV events

Ridker PM, et al. N Engl J Med. 2000
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Women andCoronary Artery Disease (CAD)

• Diagnosis and Prognosis

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Diagnosis and Management of CAD in Women

• Gender differences presentation, manifestation,
  and diagnosis of CAD
• Gender differences in mortality
• 63 of women who die suddenly from CAD had no
  prior warning symptoms
• 42 of women vs 24 of men will die within
  1 year after MI
• Thus, early recognition of symptoms and accurate
  diagnosis of CAD is of great importance

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Heart Disease in Women Lessons From the Past
Decade

• The importance of studying gender-specific
  aspects of CAD have helped in the following
  clinical dilemmas
• At Presentation of CAD women are older than men
• Less specific clinical manifestations of CAD in
  women
• Greater difficulty in diagnosis women gt men
• More severe consequences on MI when it occurs in
  women

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Screening for Heart Disease

• What Tests Should we use to identify Coronary
  Heart Disease?

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Limited Representation of Women in Studies of CAD
Testing
Adapted from Shaw LJ, et al. Coronary Artery
Disease in Women What All Physicians Need to
Know. 1999
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Are There Gender Differences in Noninvasive
Diagnostic Tests?

• Is There a Difference in Diagnostic Accuracy of
  Noninvasive Tests?

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Noninvasive Testing Options
Stress
ECG
Stress
Echo
Stress
MPI
EBCT
PET
MRI
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Noninvasive Testing in Symptomatic Women

• Stress electrocardiography (ECG)
• Stress echocardiography (ECHO)
• Stress nuclear imaging (MPI)

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Exercise ECG (Treadmill)

• Despite advances in technology, the exercise ECG
  remains an important tool in the diagnosis and
  prognosis of the patient suspected of having CAD
• The exercise ECG has an overall sensitivity of
  68 and a specificity of 77 for the detection of
  CAD in men
• The sensitivity and specificity of the exercise
  ECG in women are about 61 and 70 respectively

Kwok Y, et al. Am J Cardiol. 1999.
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ECG Testing in WomenSensitivity and Specificity
No. ofWomen
Study, Year
Sensitivity ()
Specificity ()
Detry et al, 1977 47 80 63 Weiner et al,
1979 580 76 64 Barolsky et al,
1979 92 60 68 Friedman et al, 1982 60 32 41 Guit
eras et al, 1982 112 79 66 Hung et al,
1984 92 73 59
Adapted from Heller GV, et al. Nuclear
Cardiology State of the Art and Future
Directions. 1998
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Gender Differences in Exercise ECG Testing

• ? sensitivity in women gt65 years
• ? specificity in women on hormone replacement
  therapy
• ? false-positive results due to
  autonomic/hormonal influences
• Digoxin like effect of estrogen

Shaw LJ, et al. CAD in Women What All Physicians
Need to Know. 1999
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Diagnosis of Noninvasive Tests in Women

• ECG
• Nuclear perfusion study
• ECHO poor window problem
• Dipyridamole injection MPI,
• Stress (Tread mill) Echo
• Dobutamine infusion Echo
• Computed tomography
• MR coronary angiography

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Nuclear Imaging in Women

• Myocardial perfusion imaging (MPI)
• Large body of evidence in women
• Gender-specific data available for Tl-201and
  Tc-99m tracers
• Tc-99m tracers agent of choice for women due to
  decrease attenuation artifacts from breast tissue
• Gated single-photon emission computed tomography
  (SPECT) provides post stress ejection fraction
  and regional wall motion ? helpful to reduce
  false positives
• IV adenosine/dipyridamole stress provides
  comparable overall accuracy in women and men

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Comparative Test Statistics on Diagnostic
Accuracy in Women
Kwok Y, et al. Am J Cardiol. 1999
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Diagnostic Specificity Stress ThalliumTl-201 vs
Tc-99m Sestamibi

• Perfusion imaging
• Regional blood flow
• Robust evidence in women
• Gender-specific data for Tl-201 and Tc-99m
  sestamibi or teboroxime
• Tc-99m sestamibi is agent of choice for women
  (reduced breast attenuation)
• Gated SPECT
• Post-stress EF and regional wall motion
• Reduce false-positive tests
• Pharmacologic stress helpful in older and obese
  women

N 115, P .0004
21 false
10 false
Hachamovitch R. et al. J Am Coll Cardiol. 1996
Amanullah AM, et al. Am J Cardiol. 1997
Taillefer R, et al. J Am Coll Cardiol. 1997
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Pharmacologic Stress Testing in a Community
Setting Women vs Men
Percent of patients referred for MPI who
underwent exercise stress vs pharmacologic stress
at Mission Internal Medicine Group, Mission
Viejo, CA (4/21/02 to 8/29/02)
Data provided by Greg Thomas, MD, Mission
Internal Medicine Group
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ECHO Testing in Women

• Overall
• Convenient/readily available1,2
• Avoids ionizing radiation2
• Identifies cardiac structure and left ventricular
  function (LVF)
• Sensitivity and specificity vs ECG testing1,2
• Increased sensitivity (79-88)
• Increased specificity (77-86)

1. Williams MJ, et al. Am J Cardiol. 1994 2.
Marwick T, et al. J Am Coll Cardiol. 1995
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PET Imaging for CAD in Women

• Positron Emission Tomography

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PET Case Study Patient FF
Stress
Rest
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PET Case Study Patient FFIschemia of Lateral
Wall
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Electron Beam Computed Tomography (EBCT)

• Resting study only
• Stationary tungsten target permits rapid scanning
  
• Detects coronary calcification
• Abnormality defined as presence of any calcium

Courtesy of Howard Lewin, MD, of San Vicente
Cardiac Imaging Center
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Diagnostic Accuracy of EBCT Coronary Calcium
Scores by Gender Subsets
Men
Women
Women
Men
Devries S, et al. J Am Coll Cardiol. 1995.
Rumberger JA, et al. Circulation. 1995. Detrano
R, et al. Am J Card Imaging. 1996.
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Technetium-99m SPECT Imaging Predicts Cardiac
Mortality in Women
Marwick TH, et al. Am J Med. 1999
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hs-CRP, Lipids, and Risk of Future Coronary
Events Women's Health Study (WHS)
Quartile of hs-CRP
Quartile of TC HDL-C
Ridker PM et al. N Engl J Med 2000342836-843.
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Risk Factors for Future Cardiovascular Events WHS
Lipoprotein(a) Homocysteine IL-6 TC LDL-C sIC
AM-1 SAA Apo B TCHDL-C hs-CRP hs-CRP
TCHDL-C
0
1.0
2.0
4.0
6.0
Relative Risk of Future Cardiovascular Events
Ridker PM et al. N Engl J Med 2000342836-843.
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Womens Health Initiative Trial of Estrogen
plus Progestin

• 16,608 women randomized
• Conjugated equine estrogens 0.625 mg/d
  medroxyprogesterone acetate 2.5 mg/d vs. placebo
• Primary outcome nonfatal MI or CHD death
• Primary adverse outcome breast cancer
• Stopped early (mean follow-up 5.2 years) because
  health risks exceeded benefits

Writing Group for the WHI Investigators. JAMA
2002288321-333.
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Risks and Benefits of Estrogen/Progestin on
Clinical Outcomes Womens Health Initiative
Outcome Hazard Ratio Nominal 95 CI Adjusted 95 CI
CHD (MI, coronary death) 1.29 1.021.63 0.851.97
CABG/PTCA 1.04 0.841.28 0.711.51
Stroke 1.41 1.071.85 0.862.31
Venous thromboembolic disease 2.11 1.582.82 1.263.55
Total CVD 1.22 1.091.36 1.001.49
Cancer 1.03 0.901.17 0.861.22
Fractures 0.76 0.690.85 0.630.92
Death 0.98 0.821.18 0.701.37
Global index 1.15 1.031.28 0.951.39
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Absolute Excess Risks and Absolute Risk
Reductions per 10,000 Person-Years Womens
Health Initiative
Difference in risk per 10,000 person-years
CHD events 7
Strokes 8
Pulmonary embolisms 8
Invasive breast cancer 8
Colorectal cancers 6
Hip fractures 5
Global index 19
Writing Group for the WHI Investigators. JAMA
2002288321-333.
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Treatment differences

• Thrombolysis equally effective Cerebral
  hemorrhage risk is more
• Low rates of coronary angiography in women
• Under referral for revascularization procedures
• CABG - gt operative mortality 1.9 v/s 4.6
• Restenosis after PTCA, or CABG occlusion rates
  are more for women - ? Smaller lumen sizes

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Summary

• Presentation and symptomatology
• Cardiac risk factors differences
• Metabolic syndrome, Obesity IR DMII
• Dyslipidemia patterns
• TMT lower value
• Stress Echo, MPI, Sistemibi, Dobuatamine
• CABG, PTCA risks, long term
• Above all need for greater clinical suspicion

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Take-Home Messages

• The majority of risk factors for CAD can be
  improved by lifestyle modification.
• Goals for optimal levels continue to decrease
  with each new guideline version.
• The gap between average and optimal will
  continue to widen unless lifestyle modification
  is adopted more successfully.

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Take-Home Messages

• Diet, exercise (attaining ideal body weight), and
  smoking cessation are key lifestyle changes.
• No quick-fix
• Extreme changes are usually not sustainable
• Medications are not an antidote to an unhealthy
  lifestyle

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Take-Home Messages

• Work with your patient to set realistic goals.
• Remember that modest changes in diet, weight, and
  exercise can have a big impact on cardiac risk.
• A heart-healthy lifestyle should be encouraged
  from youth, but even changes later in life lead
  to important benefits.